The present invention relates to the use of certain compounds, specifically cyclooxygenase-2 inhibitors (hereinafter referred to as “COX-2 inhibitors”) for the treatment and prevention of tumors and tumor-related disorders and cachexia.
Cachexia is a systemic disease of which the cardinal symptoms are progressive weight loss, anemia, edema, loss of appetite and so forth. It may occur as a side-effect of certain chronic diseases, such as malignant tumors, tuberculosis, diabetes, blood diseases, endocrine diseases, infections and acquired immune deficiency syndrome. When cachexia occurs as a result of the presence of a malignant tumor, even if the administration of antitumor drugs to the patient with malignant tumor is effective and antitumor effects are experienced, there is normally no improvement in the cachexia because of adverse effects such as the myelotoxicity which may be caused by the antitumor drug.
The treatment of cachexia is often very difficult for the following reasons:
Since the strength of a patient is greatly depleted as cachexia progresses, it may become impossible to continue treatment using antitumor drugs (which generally exhibit a high level of toxicity), and this thereby becomes an obstacle to the treatment of the malignant tumor.
Nutritional supplements are often given in order to treat the symptoms of cachexia. This, however, often enhances the progress of the malignant tumor, and may shorten the survival time of the patient.
At present, no satisfactory treatment for cachexia has been established, and there is an increasing need for agents that alleviate the symptoms of cachexia.
The compounds of formula (I) or (II), shown below, which, with certain other compounds, are the active ingredients of the compositions of the present invention, are known to inhibit selectively cyclooxygenase-2 (COX-2). They are also known to inhibit the production of inflammatory cytokines (particularly IL-1 and TNF-α), to inhibit the production of leukotrienes (particularly LTB4), to inhibit bone resorption, and to have analgesic, anti-inflammatory and anti-pyretic effects (European Patent Publication No. 799 823A). 
It has not previously been known that these compounds can be used for the treatment or prevention of cachexia.
Also, although it is known that certain other active ingredients employed in the present invention, namely the compounds of formula (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) and (XIV) have selective inhibitory activity against cyclooxygenase-2, an inhibitory effect on the production of inflammatory cytokines (particularly IL-1 and TNF-α), an inhibitory action on the production of leukotrienes (particularly LTB4), an inhibitory action on bone resorption, an analgesic action, an anti-inflammatory action and an antipyretic action [International publication number WO95/00501, J. Med. Chem., 40, 1347 (1997), International publication number WO94/13635, Pharmacology, 55, 44 (1997), Prostaglandins, 47, 55 (1994), Japanese publication number Hei 9-52882, Jpn. J. Pharmacol., 67,305 (1995) , Inflamm. Res., 47, Suppl. 3, S257 (1997), J. Med. Chem., 38, 4570 (1995), U.S. Pat. No. 5,474,995, European Patent No. 863 134 and International Patent Publication No. WO 98/06708], it has not previously been disclosed that these compounds have an effect against cachexia.
It is known from epidemiological studies that the taking of conventional NSAIDS (non-steroidal anti-inflammatory drugs, which are COX-1 and COX-2 inhibitors), the most common of which is aspirin, and the incidence of colon cancer have an inverse correlation. In addition, there have been many reports that NSAIDS, such as aspirin and sulindac, have shown inhibitory activity against tumor metastasis and carcinogenesis in preclinical studies. Some NSAIDS have been used in clinical studies for the prevention of colon carcinogenesis.
However, since conventional NSAIDS are not selective for COX-1 or COX-2, the occurrence of adverse effects is unavoidable.
It would, therefore, be desirable to discover a selective cyclooxygenase-2 inhibitor (selective COX-2 inhibitor) for use as an anti-tumor agent that has a low level of adverse effects.
Among the known selective COX-2 inhibitors, it is known that MF-tricyclic [Oshima, M. et al. “Suppression of Intestinal Polyposis in APCΔ716 Knockout Mice by Inhibition of Cyclooxygenase 2 (COX-2)”, Cell, 87, 803-809 (1996)] and celecoxib (Reddy, R. S. et al. “Evaluation of Cyclooxygenase-2 Inhibitor for Potential Chemopreventive Properties in colon Carcinogenesis”, Cancer Res., 56, 4566-4569 (1996)] inhibit the occurrence of experimental colonic polyposis, and that SC-58125 exhibits growth inhibitory effects against certain types of human colon cancer cell lines (Sheng, H. et al. “Inhibition of Human Colon Cancer Cell Growth by Selective Inhibition of Cyclooxygenase-2”, J. Clin. Invest., 99, 2254-2259(1997)].
However, in the case of the former, the experimental system used is not a model for an established colon cancer, and the compounds are only able to prevent the occurrence of polyposis in the preliminary stage of colon cancer.
On the other hand, with respect to the latter, the only colon cancer cell line in which growth inhibitory effects against human colon cancer cell lines have been observed is a cell line that expresses cyclooxygenase-2 (human colon cancer cell line HCA-7), and it has been disclosed that colon cancer cell lines that do not exhibit tumor growth inhibitory activity (HCT-116) in vitro do not exhibit tumor growth inhibitory effects in vivo. Thus, whether or not COX-2 inhibitor-induced tumor growth inhibitory effects on colon cancer are expressed in vivo depends on the sensitivity of the colon cancer cell lines used against COX-2 inhibitor-induced cell growth inhibitory activity in vitro. It is thus unlikely that the tumor growth inhibitory effects of COX-2 inhibitors in vivo would be observed against various other cancers, especially those cancers, including colon cancers, that are resistant to COX-2 inhibitor-induced inhibition of cell growth in vitro and that do not express cyclooxygenase-2.
Moreover, there has been no previous disclosure of the use of a combination of a selective cyclooxygenase-2 inhibitor and a 5-fluorouracil derivative for the prevention or inhibition of tumor growth.
We have now found that certain 1,2-diphenylpyrrole derivatives and closely related compounds have excellent activity for the prevention or inhibition of cachexia, and that these 1,2-diphenylpyrrole derivatives are effective for the treatment or prevention of tumor-related disorders, alone or in combination with a 5-fluorouracil derivative.